Abstract 6113: Predictive value of HRD testing on the response to PARP inhibitors in ovarian cancer preclinical models
Authors: Giulia Dellavedova, Alessandra Decio, Laura Formenti, Luca Porcu, Carmen Ghilardi, Raffaella Giavazzi, Maria Rosa Bani
Journal: Cancer Research (2023)

Abstract Since the introduction of Poly(ADP-ribose)polymerase inhibitors (PARPi) in the clinical practice, the search of biomarkers to distinguish homologous recombination defective tumors, eligible for PARPi therapy, has become a priority. Along with testing for BRCA mutations, commercially available tests, such as MyChoice® assay (Myriad Genetics), exploit scores calculated from genomic scarring patterns. Platinum sensitivity is also considered a surrogate marker of PARPi efficacy. However, the prognostic accuracy remains a challenge because these tests can only infer homologous recombination functionality but not directly measure it. Moreover, the association between platinum and PARPi response is imperfect since not all platinum-sensitive patients benefit from PARPi and PARPi response has been observed in platinum-resistant cancers. A panel of 20 high-grade serous ovarian carcinoma patient-derived xenografts (OC-PDXs) were molecularly and pharmacologically characterized to assess predictive markers of response to PARPi therapy. Genomic DNA and total RNA were sequenced searching for BRCA1/2 alterations or sent to Myriad Genetics to obtain HRD scores. Absolute BRCA1 mRNA expression was measured by RT-qPCR. OC-PDXs growing subcutaneously or orthotopically in nude mice were treated with the PARPi olaparib or platinum to test drug sensitivity. The molecular analyses revealed that nearly 90% (17/20) of OC-PDXs are TP53 mutated, thus reflecting the clinical scenario. 50% (10/20) of OC-PDXs harbor mutations in BRCA1/2 genes, while 10% (2/20) lack BRCA1 mRNA expression. MyChoice® assay showed that 65% (13/20) of OC-PDXs score higher than 42, which is the currently used threshold to classify HRD-positive tumors. Correlation analysis confirmed that the HRD score is highly associated with the presence of mutations in BRCA1/2 genes. Preclinical testing showed that 50% of OC-PDXs are sensitive to olaparib. Notably, in 20% of cases the therapeutic response was incorrectly predicted considering either BRCA1/2 mutations or HRD score. 30% of platinum-sensitive OC-PDXs were not responsive to olaparib, confirming that platinum sensitivity not always correlate with response to PARPi. Our results show that tumor genotype and HRD score are strongly associated. Further analyses are required to improve the predictive value of currently used tests to select patients who will benefit the most from PARPi treatment while sparing toxicities in patients that are unlikely to respond. Citation Format: Giulia Dellavedova, Alessandra Decio, Laura Formenti, Luca Porcu, Carmen Ghilardi, Raffaella Giavazzi, Maria Rosa Bani. Predictive value of HRD testing on the response to PARP inhibitors in ovarian cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6113.